Psoriasis is characterized by keratinocyte hyperproliferation, loss of granular layer and parakeratotic differentiation. Caspase-14 is a nonapoptotic caspase family member whose expression in the epidermis is confined to the suprabasal layers, and is associated with terminal differentiation. In normal skin, caspase-14 is detected in the cytoplasm and nuclei throughout the suprabasal layers. However, in the parakeratotic regions of psoriatic skin, which are characterized by the lack of nuclear destruction, caspase-14 expression is down-regulated. Strategies to upregulate caspase-14 expression may constitute a novel therapeutic contribution to diseases involving parakeratosis, including psoriasis. Agents that lead to differentiation of epidermal keratinocytes may have therapeutic effects against psoriasis and could also be useful in wound healing and other hyperproliferative skin disorders. Thus, identifying a naturally occurring Complimentary and Alternative Medicine approach with a agent that induces differentiation of epidermal keratinocytes without inducing apoptosis is a highly desirable goal. Delphinidin, a major anthocyanidin in pigmented fruits and vegetables, possesses potent antioxidant activity. Recently, we have shown that topical application of delphinidin inhibited ultraviolet B-mediated formation of DNA damage and TUNEL-positive cells in SKH-1 hairless mouse skin. However, no studies have examined the impact ofdelphinidin treatment on the function of normal human keratinocytes. Our preliminary unpublished studies are noteworthy where we have demonstrated that delphinidin induces procaspase-14 protein and mRNA expression in normal human epidermal keratinocytes. We also found a significant increase in the protein and mRNA expression of involucrin and transglutaminase-1. It is noteworthy that delphinidin under identical treatment conditions did not result in induction of apoptosis. This remarkable distinction forms the basis of this application which is designed to investigate the effect of delphinidin on keratinocyte differentiation both in in vitro human reconstituted skin model system and in preclinical in vivo settings. The central hypothesis to be tested in this application is that "delphinidin will reduce the pathological markers of psoriasiform lesions by inducing the expression of caspase-14, and other markers of early and late differentiation and by suppressing cell proliferation without inducing apoptosis". To test our hypothesis, the following specific aims are proposed: (1) To investigate whether delphinidin treatment increases the distribution and expression level of keratinocyte differentiation markers in in vitro three- dimensional human reconstituted skin as an experimental model system that allow complete epidermal differentiation, and (2) To examine the effect of topical application of delphinidin on pathological markers of psoriasiform lesions under in vivo situation employing flaky skin (fsn/fsn) mice and flaky skin (fsn/fsn) caspase 14-/- mice. Studies will be conducted to determine whether caspase- 14 expression is associated with reduced symptoms of epidermal pathology. PUBLIC HEALTH RELEVANCE: This application intends to define a novel agent delphinidin present in pigmented fruits and vegetables for the treatment of psoriasis and could also be useful in wound healing and other hyperproliferative skin disorders.